PL159837B1 - Method of obtaining of phtalansine-acetic acid - Google Patents

Abstract

1. A method of producing phthalazine-acetic acid of the formula 2, characterized in that the compound of the formula 3 is reacted with hydrazine in the presence of a solvent, unreacted hydrazine is removed and the mixture is reacted with an acid in the presence of a solvent - switch. P L 159837 B 1 Model 2 PL PL PL

Description

The present invention relates to a process for the preparation of this Iwasu ftalazynnoc ^n, u ^foo holiday season for the preparation of a certain derivative of ^y ch ch ^{k y k} et Vasu; ofdlazynoocdwego and esters thereof.

Ester derivatives are of the formula ftalazynoocdwego olcreslone ^{4 wk} tórym R represents a ^roup E / CJ-C ^ / alkjLnową. In the process of the present invention, a compound ^P o; ^^ ^ vym of a new yeah l-hydrazino-1,2, ^{3 »4»} tetrahydro ^{ydr o-4} ~ ^k ^ O etoftalazynooc of formula 1.

Certain acids cyclical heteroc ^{y k y} etoftalaz nylncctowe and estty of wztim 5, wherein ^χ is oxygen or sulfur, ^G rupa NH or CH ^R is a group? h ^y droksylową or ^a rupa prodrug thereof, R ² is ^a rupa ^h etemcykliczną, R and are hydrogen or the same or different, and ^R mma ^and volume hydrogen or Nupe methyl and ^p ewne acceptable pharmacological ^and Ichnya salts, and the at ^foo tecznośó as inhibidrów reductase aldeozowe;) u ^j and ⁿ iono in removing paten ^ tcjwym ^S dances jednoczonych Patent No. 916 121 ⁿ a white October ^7, 1986 ^r., which is a drift isolated from ^a niechanego current drift No 796 039 filed ⁷ Nov. ¹⁹ 85 ^{r., f} Tore ^{of DP} sponds drift to the ^p atenta European # ² 22 ⁵ 76, a ^p ublikowanemu May ^{20 19} 87 y. Said elimination of ^p atentowe also discloses a s ^ method for preparing p-different ^e Ministers kiMSU italaz ^ oocUwego, ^kt Ory comprises reacting ^ wnych dzwdtków phthalate or z / carbo tokayme you leno / t rójfnny Ώοι os ^ mem either / karbometo ^k ^ ymeiyleno ^of tΓÓjίenylo ⁿ os ^of OΓynem Wittig reaction, followed reaction is kept ^ choamych ester of acetic acid z ^ ^ ^ drazyn preferably in ^water n in a solvent at a temperature of ⁴ 0-12O ° ^C

S ^ method for manufacturing twasu / Z / -3-oxo-l / HA / -izodnzofuranylidenooctowego anhydride ftadwego ^p slaughter putting the anhydride reacted with ^o su CTAN and dzwonnikiem acid was isany O ^{p p} slaughter dhrnedera ^Η · Ε · ^s and p. ⁱⁿ J. Amer. Chem. ^S oc., TQ, ⁴ 46/1956 /.

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A process for preparing p'ewnych phthalazones by reacting aldehydokwaau ortoftalowago acid or the ^h ftalooowego ydrazyną has been described by ^Va ng ^h ana WR and Baird, Jr., ^S .L. in J. Amer. Chem. ^S oc., 68, 1314/1946 /.

Foldeak S. and wep. in Chemical Abstracta 72 »1.00626p (1970), Khim.-Farm. Zh., 3/12 /, 5/1969 / disclose, inter alia ^p s oaób preparation bass ⁴ / 3H / -ftalazono-jl-CCT ^ ^ in it by heating the acid / Z / -3-oxo-l / 3H / - izobenzo ^f ur ^and nylld ^{EoO C} for 2 points during odzin ^g of L ^ H ^ ^ -HgSO in wodoym solution KHCOy

S ^p of the invention for preparing ftalazynooctowego acid of formula ^{2 in the} lega ° and the reaction of the acid / Z / -3-oxo-l / 3H / -izobznfufuoanylidenooctowego ^{head of} the sculpture 3 with hydrazine in the presence of a solvent to otrzymaba located alongside of ^the rniemniny ^of these ^g of compound fOR IN Jsc ^ acid, l-hydrazino-1-2, ^{3, 4} ~ tetrahydrn-4-oxophthalazineacetic acid of formula ¹ and ^{3-, 4} -dihy ^d ro ~ ^{4 f} k ^s is talazynooctowego formula ^2, the reaction of the resulting ^p s of the mixture with an acid ^{in about} becności solvent to ^p rzekształcenia of l-hydrazino-l, ^{2, 3,} 4-tetrahydro-4-ketoftalazynooc ^ acid in 3,4-dihydro-4-oxo-phthalazineacetic.

The process according to the invention involves several steps, which point to ^the ano as ^e taps numbered 1-4 ^h emacie sc oa oa ryauo ^k u. The starting ziNiązek ^of iwzorze 3 aie replaced with phthalic anhydride, acetic anhydride and ethyl ^p otaau according to the reaction described by ^S chroe <iera et al., ^J. Amer. Chem. ^S oc., 78,

446/1956 /. In reaction step ¹ / Z / 33_keoo-l / 3H / -izobennf ⁱⁿ uranylidenooctowy of formula 3 is reacted in a suspension of pyrazin ^hyd in the presence of a solvent. Suitable solvents are the ^angle e, in which the reactants are at least partially soluble. Preferably, u ^y holiday season such solvent is a lower alkonol and most preferred is ethanol. ^J owever be odkreślió ^{p, e} may be used other suitable spread uszczalniki ^{p, k} inert under the conditions of reaction s. Decision of ^K · ^y stne is equal to that of ^tears in the reaction of ² molar equivalents yolk drazyn ^{hy s. In} view of the e e ^g zoterrnicznośó reaction mixture temperature rea tive ^k increases. Therefore, in order to reduce formation of undesirable aie ^{p hyd} razydu irazolonu and having a blast ^ ^ tydrazyn reaction temperature re ^g uluje such that ^the temperature so as not forgave chine ⁴ 0 ° C. .Jeszcze ^b Arda is advantageous to control the reaction temperature in the range of ^or about 20 ° ^C to about 30 ° ^{C, I} n the range of temperatures of from about ² to 5 ° C and 30 ° C chine even brzystnie jszy. Reaction ¹ eta pu ^d AJE as pro ^d UK1; a mixture of potassium 3,4-dihydro-4-ke fftalazynooctowego ^of formula 2 ^ and the new compound, 1-hydrazino-l, ^{2,3,4-tetra-h} ydro 4- etoftalazynooctowego ^angle of formula ^1, the mixture can be Bora recovered by filtration, washing and drying using procedures well known to those skilled in the art, this mixture being obtained in the form of a solid.

Although some conditions of isolation ^ h there is a loss ^hy <irazyny from a compound of formula ¹ and O borzeniem compound of formula ^2, it nevertheless now ^Y compound, acid, 1-hydrazino-l, 2,3, ^{4-tetrahydro-4-} ketof tabzynooc towego of formula 1 are useful in the preparation of the ester of formula 4, since the ^Eb isolated the baby monitors it with the mixture of tasern 3, ^4-di hyά3 ^? o ^ 4-kenff talzoyr ^ o ^ c (^-Community of formula ² is not is neither itonieczne or brzystne ^ for the use of a compound of formula 1 and / or ^ ^ eal crossing sposotiu invention. Yi conditions described herein ac ^{k h them} if the acid / Z / ^ -3-oxo-3H / -izoomzufuranyledenooct <head of formula 3 is subjected to "action ^{with hy} drazyną is obzymuje mixtures containing ^80% of a compound ^of formula ¹ and? 20% of the compound of formula ² as found in the sample of analyzed Liure.

159 ^p 837 of the receipt of the compounds of formula ¹ and formula 2 by ^one step reaction, a mixture of l-hydrazino-l-2-3-4 tearahydro-4-oxophthalazineacetic acid of formula ¹ and taasu 3,4-dihydro-4-oxophthalazineacetic acid of formula ² is reacted in the presence of an acid and a solvent of the formula AOH, ^k in the group oizacza tórym a / C ^ C ^ / alkćową. This reaction as determined by Scheme rysuz ^k of the step 2 and give a mixture of ^p rodulct ^k Vasu 3,4-dih ^y dro-4-ketoftaliz ^ ooctwwego Formula ² and an ester of formula 4 ·

It is preferable to use anhydrous dilohydric acid in step ² . Yet ćrdziej k ori ^y it is preferable to use about 0.1 mole equivalent of ^b eiwodne ^g of towasu ćlorowodorowego reakyjnej and heating the mixture to a temperature of wrienia solvent reflux iwrotną ^p · ^{J k} esicze tiardziej stne Decision of ^y is used as roipuszczalnika methanol or ećnolu.

The following are illustrative rzykłady ^p s ^p pro person by wynalaiku, wherein ^p riykład I illustrates wytwarianie iwiązku output. Magnetic resonance spectra of a photon ^{y a} la handwriting measured on solutions in deuterated dwurnetylosulfo oxide / DMSO-d / ^p and live long ików cięściach expressed in ppm / ppm / w ^{d p} oc ol ola tetramethylsilane. Shapes ^p ików oinaczano as follows: S-einglet, t, triplet, q, quartet; m, multiplet.

Example I. ^K was / Z / 33-keto-1 / 3H / -ibobenzofuΓznylidznoactow ^y . To ⁴⁰² ml / 4.26 mol / acetic acid was added ćzwodnika 3.50,0 ^g / 1.01 mol / t) and eiwodnika fćlwwego 1 ² 4 g / 1.26 mole / of ethyl ^p otaau in a ² liter flask trójai ^y jnej. iawiesinę held heated at tempera Time ¹ 3-O-135 ° C ^{1 g of p} slaughter odzinę 20 minutes and then cooled tempera ^d of round 75-80 ° C and ¹⁵ ° 0 ml of toluene. ^P oiwolono slurry to cool to 30 ° ^C and winding βΐβΐ ^ ^y ^ ί βηο ¹ hour. The solid odiyskano ^p slaughter filtration ^p rzernyto ³⁰⁰ ml of methylene chloride and dried in owietrzu ^{p. O} susione solid iawieezono jponownie in 15 ml of 0 ° H tempera turn ^it into ² 0-25 ° C, for ^{k p} oiwolono rystalizację for 1 ydziny and Susi it in the dryer and ^pneumatic part fzepyywem at? ^P slaughter ° C overnight, to give the compound tytuoowy and ^2% yield of 5 / l0 ^0, 0 ^grams /. The temperature to pressure ^{p 2} 45-25O ° C. N ^KR / DŁiSO-dg, 60 mHZ /: 67.68-8.5 / m, 4, Ar-H /, 6.33 / β, Ι, H> CC /.

Example II. tas thalazinooct; <) O and Itwas ^^ drazynn-l, ^2, 3, ^{4-tetrahydro-4-oxo} talazynooctow ^{of y.}

A. / 1 / To ² 5 ml of ethanol / 2B / in 5 ° ml of itolMe bottom was added ² g / 132 Mnol / Iraasu / Z / -3-keto- ^1H 3H) risoblrooflzanyl ^from enoacetate. To the resulting suspension was added during ¹⁰ minutes ^11, 8 ml of a 54% solution of ^{hydroxypropyl} dniyny / \ y 2 mmol / ethanol / 2B / in ² tempera round 5 ° C. The mixture was stirred ³⁰ minutes and jrnbrano ^p excipient to thin layer chrwMtografii / TLC and / Pri ^y moths as a phase roiwijającej system c ^h loroίoΓm / metanrl / acetic acid 4: 1: 2, ^k Tor this analysis revealed ^e obtained two ^p rodukt ^y . ^In awiesinę was ods ^ iono, ^p rzemyto 50 ml of ethanol / 22 / and susiono in the drying ^p ro ^with ~ n and o and ^p r: ep ^y ywem aiotu at ^{4 0} C to give ²⁵ 2 ^g of the solid mixture Chromaćgrafia cisnkowarsćowa and at ^f ycieQ chloroform / methanol / acetic itwasu 4: 1: 0.1 showed ie solid mixture consists of d and ^{C p h} completely olarnych iwiązków. More olarnym iwiązk ^p ^ ern ^to wit iwi ^± IEC was wrapped as ^{k 3, 4-dihydro-4-ke} Uf talazynoocowwy ^p slaughter C ^OMPARISON and an authentic sample by ftrzymar.ą imyalenie fchodnej such as the ethyl ester less polar iwiązek and the miesianiny They characterized in the following ies doświadczeniac ^{p 1} ·

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A./2/ To 50 ml of methylene chloride in a 125 ml three-necked round bottom flask equipped with a mechanical stirrer, thermometer ^and condenser, ¹⁰ g of the solid mixture obtained under A (l) was added. The flask was heated at reflux condenser ctiłodnicą of ^p / 40 ° C / ¹ hour, ^a bride, lymphoma ^d of ^{d p} temperature of ojowej ^k and the contents rapidly filtered through a sintered Buctwera. The solid was washed ^d wukrotnie portions of ² 5 ^m l ^ch lorku notylenu and dried in an oven ^p różniowym of ^p sump ^y ywem nitrogen temperat ⁱⁿ sculpture deg ^co lo 4 ⁰ ° C for ^{2 g} odzin, yielding 9 g / recovery ⁹⁰ % / ^s tałej m ^^ Mny ^w ł ^a ~ strictly unchanged.

A / ^3/2 to 4, 5 mL of methylene chloride at 1.5 deg ml three-necked ^e j kdlbie ^of krągłodennej equipped with mechanical stirrer, thermometer and a condenser ano ^ext

8.5 ^{g of} the solid mixture obtained in unkcie ^p / 2 /. ^K olbę ^of the heating ^at reflux / 40 ° ^C / ^h in c, ^d Bovine ux for ¹ g ^of <lzinę ^{then p} ozwolono to cool to a temperature okojowej ^p. Content for ^the wolono for ^{1 g} odziny to ^k y ^y stalizację, then ^p rzesączono through a Buchner funnel, ^p rzemyto twice ^p orcjami after ^21, 25 ml of methylene chloride and dried in an oven próżniwwym of pirzep ^ Wem nitrogen, at a temperature ^of about ⁴ ° ⁰ C to give .8,06 ^g / recovery of 4.8% ⁹ / brown solid. TLC using chloroform / methanol / toiasu acetic acid in a ⁴ "L" 0, l once again revealed that this solid ^{enough to allow} a mixture of ^d So go ^h of compounds including the same, as described above, less polar compound ^BE dącego ^g hunted slcładnikiem . °° at 3 mHz NMR was obtained for the mixture in D ^ SO-d in addition to the corre ^ aingletu propelled by the methylene protons of ^3, 4-dJLhydro- ^ 4-ke ^of oftalazynooctowego ^I n ^δ 3.64, two protons neces ^ wnoważone methylene ^ ^ sei owano ² from 5, 74 and δ ^2, 27, which indicates ^{that the e} BRIEFINGS are related to the metric as ^white carbon, as well as funlccją acid. By analysis the solid mixture contained 3.7% nitrogen, ^2, demonstrate ^{e d} was included ruga part ^± molecule ^{hy d} piperazine. ^From these analytical ^d rations defined Building an ^e bound of the second novel ^± relationship, L.- acid ydrazyno ^{h-l, 2,} 3,4-tetrahydro-4- ^y dro ^k etoftalazynoocowwego of formula ¹ "

Example III. TOIA 3, 4-dlhydro-4-ke t of the head and talazynoo ^ ^k ^ was ydrazyno-l, ^2, 3, ^{4--tetΓahydro} 4kkeiof talazyniociowy.

To ⁵⁰⁰ ml of ethanol (2B) in a ¹ liter three-necked solution was added ⁵ ° C, 0 ^g (1262 µm (Irnasu / Z) -3-metho-1 (3H) -ibobenzofuranylideneacetic acid. Followed by the addition of ^{d k y} OLB, within ¹ C-15 hnut 31 ml / 526 miiicdi, 2 eq / ⁵ tyiirazyny 4.4% ethanol / 2B /, and the mixture tempera ture rea ^k c ^y ^ jnej wzrt Votes ^{d 41} ° C with a shell ^ uo ^g zotermiczniści reaction .. ^{Z p} slaughter awiesinę stirred ¹ .5 h at 25-30 ° C rzesączono ^{p, p} rzemyto MO ml of ethanol / 2B / and dried overnight in a drying ^p różniowej ^p rzepływem with nitrogen at ⁴⁰ ° C to give 51.79 ^{g of} a mixture of the title ^ Outgoing compounds.

Example IV. foaa 3, ^ dihy ^ o ^ -ke toi? talazynioc ^and alive and baa ^and - ydrazyno ^{h-l, 2,} 3, ^{4 y} of Road -tetrah ^4-oxo talazynooctow ^{y 0.}

0 ^{to 50} ml of ethanol / 2Ά / in a ¹ liter three-necked oltile ¹ and ^{k 1} ano 31.0 ^g / 263 imnoli / acid / Z / -3-ke to-3H 0 / -lzobznzoiaranymdenooctwwego. ^ e ^ instep dofono slowly over ¹⁰ m ^ ut, ^{4 23} ml of 5% sodium ^hyd piperazine / 395 landmines / ethane ^ u / 2B /. The reaction temperature rose ^d 42 ^O C ^ du ogzotormicziiści the reaction of the ^p prnzwolono to cool at room temperature for ^d and I ^e was stirred for ¹ 5 hours. The solid obtained was separated by filtration, washed with ml of ethanol WO / 23 / ^p slaughter and dried overnight in a vacuum iecu ^p ^ Wem flow ^of azotiu at 4 ⁰ ° C to give 47.14 ^{g of} a mixture ^of the title zmązków those in ^p ostaci solids.

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Example 5 3,4-Dihydro-4-ketophthalazine acetic acid. V 500 ml, three-necked round bottom flask equipped with a meehhical stirrer, thermomeer, thermal clock and a heating mantle under a nitrogen atmosphere of 250 ml of ethanol (2B) and 25 g (0.106 mol) of a mixture of 3,4-dihydro-4-ketophthaazinoacetic acid and 1-hydrazine-1,2,3,4-tetlahyd-1-4-ketofalzinolctic acid. Then 1.929 g (0.053 m 3 · 5 eq. HCl) were bubbled into 50 ml of ethanol (2B) and this solution was added to the flask. The flask was heated to 60 ° C and the reaction was allowed to proceed for approximately 32 hours, after which a sample was taken and lithium by thin layer chromelotralfi (TLC) (chloro! Omi / methanol / acetic acid in a ratio of 12 "3"). l / at 254 nm.

TLC analysis showed no l-hydrazinGo acid remained. ^2, 3,4-tetnhydrot4-oxo-phthalazineacetic, but was present mainly 3,4-dlhydΓo-4 - etoftaazznnooctowy with some of its ethyl ester, which was also present.

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Formula 2

Pattern L.

Scheme

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Department of Publishing of the UP RP. Circulation of 90 copies. Price: PLN 10,000

Claims (4)

Patent claims 1. S ^p of the preparation of the formula ftalazynooctowego 2, characterized in that the compound of formula 3 ^p calls is reacted with hydrazine in the presence of ^p spread uszczalnikt is removed nieprzeraagowaną ydrazynę ^h and a mixture of ^p calls with an acid in the presence of a size uszczalnika ^{p. 2} · ^A process as claimed in claim. !., Wherein ^e is used, about ^two molar equivalents of ^y h drazyny and the acid is bezwo ^d ny ^{y k} was Soln. 3. ^Sp Osoo claim. 2, characterized in that the anhydrous hydrochloric acid is used in an amount of about 0.1 molar equivalents and the mixture reakce ^y jna onzewa to reflux a size of ^{p p} uszczalnika reflux. 4. ^Sp persons according to p. 3, wherein ^e is used as solvent methanol or ethanol .. * * *